What additional investigations are recommended for a patient with worsening fatigue and subclinical hypothyroidism?

Additional Investigations for New Hypothyroidism Workup

For a patient with confirmed subclinical hypothyroidism (TSH 5.98, free T4 10.1) and worsening fatigue, you should immediately check morning cortisol and ACTH to rule out central hypothyroidism and adrenal insufficiency before initiating thyroid hormone replacement. 1

Essential Initial Investigations

Thyroid Antibodies

• Thyroid peroxidase (TPO) antibodies should be measured to identify autoimmune thyroiditis and predict progression to overt hypothyroidism 1, 2
• Positive TPO antibodies increase the risk of progression from subclinical to overt disease and support the decision to treat 3, 2

Pituitary Function Assessment

• Morning (9 AM) cortisol and ACTH levels are critical to distinguish primary from central hypothyroidism 4, 1
• If TSH is inappropriately normal or low relative to a low free T4, this suggests central hypothyroidism requiring pituitary evaluation 1
• This must be done before starting levothyroxine, as thyroid hormone replacement can precipitate adrenal crisis in patients with undiagnosed adrenal insufficiency 4, 5

Metabolic and Cardiovascular Risk Assessment

• Lipid profile (fasting) to assess for hypothyroidism-associated dyslipidemia 4, 1
• Fasting glucose or hemoglobin A1c since hypothyroidism affects glucose metabolism 1
• Complete metabolic panel including electrolytes (sodium, calcium, magnesium), renal function (BUN, creatinine), and liver function tests 4

Baseline Hematologic Assessment

• Complete blood count to evaluate for anemia, which commonly accompanies hypothyroidism 4

Additional Investigations Based on Clinical Context

If Central Hypothyroidism is Suspected

• Pituitary MRI with contrast (with dedicated pituitary/sellar cuts) if multiple hormonal deficiencies are present or if TSH is inappropriately low/normal with low free T4 4, 1
• Additional pituitary hormones: LH, FSH, testosterone (males), estrogen (premenopausal females), prolactin, and IGF-1 if central etiology suspected 4, 1

Confirmatory Testing

• Repeat TSH and free T4 in 2-3 months if initial TSH elevation is mild (4-10 mIU/L) to confirm persistence, as approximately 37% of patients with initially elevated TSH spontaneously normalize 3, 2
• For your patient with TSH 5.98, this second measurement serves as confirmation of persistent subclinical hypothyroidism 2

Critical Pitfalls to Avoid

Never Start Thyroid Replacement Before Ruling Out Adrenal Insufficiency

• In patients with central hypothyroidism, hydrocortisone must be initiated before levothyroxine to prevent precipitating adrenal crisis 4, 5
• The sequence matters: assess cortisol → replace if deficient → then start thyroid hormone 1

Don't Overlook Central Hypothyroidism

• A "normal" TSH with low-normal free T4 and worsening symptoms may indicate pituitary dysfunction, not euthyroidism 1
• Your patient's free T4 of 10.1 (likely pmol/L, at lower end of normal range) with TSH 5.98 warrants cortisol/ACTH assessment 4, 1

Avoid Overdiagnosis in Elderly Patients

• TSH naturally rises with age; age-specific reference ranges should be considered in patients over 70 years 3, 2
• However, your patient's worsening fatigue makes this clinically significant regardless of age 4

Monitoring Strategy After Initial Workup

• If central hypothyroidism is confirmed, monitor free T4 levels (not TSH) and maintain in the upper half of normal range 4, 1
• If primary hypothyroidism is confirmed and treatment initiated, recheck TSH and free T4 in 6-8 weeks after starting levothyroxine 5, 6
• Target TSH in the lower half of reference range (0.4-2.5 mIU/L) for most adults 2, 6